RESEARCH SUMMARY Heart failure (HF) affects more than 5 million people in the United States, and the number increases by more than 0.5 million every year. Acute decompensated HF accounts for over one million hospital admissions per year. The estimated direct and indirect cost for HF in 2006 is $29.6 billion. Our long-term objective is to improve the prognosis of HF patients by more accurately predicting their response to cardiac resynchronization therapy (CRT) and/or revascularization. CRT has been approved by FDA as a treatment of HF patients refractory to conventional therapy. However, 20-40% of the patients who selected for CRT based on the conventional criteria do not respond to CRT. Echocardiography has shown to improve patient selection for CRT, but it requires expertise to obtain reliable results. The PROSPECT trial has shown that under real-world conditions the current available echocardiographic techniques are not ready for routine prediction of CRT response. Our primary goal is to predict the response to CRT in patients with HF-induced conduction disturbances and ventricular dyssynchrony. It will be accomplished by improved diagnosis and characterization of left ventricular (LV) dyssynchrony using our novel, quantitative multi-harmonic phase analysis (MHPA) of ECG-gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) study and by integrating this evaluation of LV dyssynchrony to our established quantification of myocardial perfusion and viability from the same study. This integrated quantification will also be used to predict the response to revascularization in HF patients with ischemic cardiomyopathy - our secondary goal. We propose to measure LV dyssynchrony from ECG-gated SPECT MPI, because 1) it is widely available, 2) it is highly reproducible, and 3) it can provide additional perfusion/viability information, which is needed for the management of the HF patient, without any additional procedure. Specifically, in this research we will 1) develop LV dyssynchrony simulation tools that can simulate gated SPECT MPI studies with a variety of LV dyssynchrony patters, 2) develop MHPA and optimize it by using the simulation tools to determine the imaging requirements for accurate MHPA measurements, 3) define and validate quantitative indices that describe LV dyssynchrony and development normal databases for these indices, 4) use the LV dyssynchrony quantification coupled with our established perfusion/viability quantification to predict the response to CRT in HF patients, and 5) use the integrated quantification of LV dyssynchrony, perfusion, and viability to predict the response to revascularization in HF patients with ischemic cardiomyopathy. Upon completion of this research, we will establish a strong scientific foundation for our phase analysis approach thus supporting a large clinical trial to prove the usefulness of ECG-gated SPECT MPI with our integrated quantification of LV dyssynchrony, perfusion, and viability in prognosis for HF patients and thus promoting widespread utilization clinically.